Therapeutic Technology and Methodology / Therapy / Gene Therapy

Specialty: Gene TherapyInstitution: Gene Therapy Center, University of North Carolina at Chapel HillAddress: Chapel Hill, North Carolina, 27599, United States

Published on January 23, 2015

Abstract: Over the last five years, the number of clinical trials involving AAV (adeno-associated virus) and lentiviral vectors continue to increase by about 150 trials each year. For continued success, AAV and lentiviral expression cassettes need to be designed to meet each disease's specific needs. This review discusses how viral vector expression cassettes can be engineered with elements to enhance target specificity and increase transgene expression. The key differences relating to target specificity between ubiquitous and tissue-specific promoters are discussed, as well as how endogenous miRNAs and their target sequences have been used to restrict transgene expression. Specifically, relevant studies indicating how cis-acting elements such as introns, WPRE, polyadenylation signals, and the CMV enhancer are highlighted to show their utility for enhancing transgene expression in gene therapy applications. All discussion bears in mind that expression cassettes have space constraints. In conclusion, this review can serve as a menu of vector genome design elements and their cost in terms of space to thoughtfully engineer viral vectors for gene therapy. ...
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Abstract: In Part I of this Review (Wang and Gao, 2014), we introduced recent advances in gene delivery technologies and explained how they have powered some of the current human gene therapy applications. In Part II, we expand the discussion on gene therapy applications, focusing on some of the most exciting clinical uses. To help readers to grasp the essence and to better organize the diverse applications, we categorize them under four gene therapy strategies: (1) gene replacement therapy for monogenic diseases, (2) gene addition for complex disorders and infectious diseases, (3) gene expression alteration targeting RNA, and (4) gene editing to introduce targeted changes in host genome. Human gene therapy started with the simple idea that replacing a faulty gene with a functional copy can cure a disease. It has been a long and bumpy road to finally translate this seemingly straightforward concept into reality. As many disease mechanisms unraveled, gene therapists have employed a gene addition strategy backed by a deep knowledge of what goes wrong in diseases and how to harness host cellular machinery to battle against diseases. Breakthroughs in other biotechnologies, such as RNA interference and genome editing by chimeric nucleases, have the potential to be integrated into gene therapy. Although clinical trials utilizing these new technologies are currently sparse, these innovations are expected to greatly broaden the scope of gene therapy in the near future. ...
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Abstract: Safe and effective gene delivery is a prerequisite for successful gene therapy. In the early age of human gene therapy, setbacks due to problematic gene delivery vehicles plagued the exciting therapeutic outcome. However, gene delivery technologies rapidly evolved ever since. With the advancement of gene delivery techniques, gene therapy clinical trials surged during the past decade. As the first gene therapy product (Glybera) has obtained regulatory approval and reached clinic, human gene therapy finally realized the promise that genes can be medicines. The diverse gene delivery techniques available today have laid the foundation for gene therapy applications in treating a wide range of human diseases. Some of the most urgent unmet medical needs, such as cancer and pandemic infectious diseases, have been tackled by gene therapy strategies with promising results. Furthermore, combining gene transfer with other breakthroughs in biomedical research and novel biotechnologies opened new avenues for gene therapy. Such innovative therapeutic strategies are unthinkable until now, and are expected to be revolutionary. In part I of this review, we introduced recent development of non-viral and viral gene delivery technology platforms. As cell-based gene therapy blossomed, we also summarized the diverse types of cells and vectors employed in ex vivo gene transfer. Finally, challenges in current gene delivery technologies for human use were discussed. ...
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Abstract: Advances in understanding the molecular basis of obesity and obesity-associated diseases have made gene therapy a vital approach in coping with this world-wide epidemic. Gene therapy for obesity aims to increase or decrease gene product in favor of lipolysis and energy expenditure, leading toward fat reduction and loss of body weight. It involves successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain energy homeostasis. Here we summarize progress made in recent years in identifying genes responsible for obesity and present examples where the gene therapy approach has been applied to treating or preventing obesity. Discussion on advantages and limitations of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of obesity and obesity-associated diseases. ...
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Abstract: Atherosclerosis (ATH) and aortic aneurysms (AA) remain challenging chronic diseases that confer high morbidity and mortality despite advances in medical, interventional, and surgical care. RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH and AA. Despite positive results in preclinical and some clinical feasibility studies, challenges such as target/sequence validation, tissue specificity, transfection efficiency, and mitigation of unwanted off-target effects remain to be addressed. In this review the most current targets and some novel approaches in siRNA delivery are being discussed. Due to the plethora of investigated targets, only studies published between 2010 and 2014 were included. ...
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Abstract: Hematopoietic stem cell gene therapy is one of the most exciting clinical tools to emerge from the gene therapy stable. This technology combines the expansion capability of hematopoietic stem cells, capable of replacing the entire blood and immune system of an individual, with the capacity for long-term replacement of one or more gene copies using integrating gene therapy vectors. Hematopoietic stem cell gene therapy benefits significantly from the pre-existing experience of standard blood and marrow transplantation, whilst at the same time having the capacity to deliver a safer and more effective therapy to a wider range of diseases. In this review we summarize the potential of hematopoietic stem cell gene therapy to expand the scope of hematopoietic stem cell transplantation, including the evolution of vector delivery systems and the success and failures of current clinical experience with this treatment. In particular we deal with the incidence of vector mediated transformation in patients and the steps that have been taken to minimize this risk. Finally we discuss the innovations in preclinical development that are likely to drive the future of this field, including the expansion to many more genetic diseases, particularly those affecting the brain. ...
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Specialty: Immunology, Gene Therapy, Oncology, PathologyInstitution: Center for Cell and Gene Therapy, Texas Children's Hospital and The Methodist Hospital, Baylor College of MedicineAddress: Houston, Texas, 77030, United States Institution: Department of Pathology and Immunology, Baylor College of Medicine Address: Houston, Texas, 77030, United States

Published on December 5, 2013

Abstract: While cure rates for several cancers have significantly improved, the outcome for patients with advanced solid tumors remains grimly unchanged over the last decades. Thus, there is a need for new therapies that could improve outcome for patients who fail current therapies. Oncolytic (cancer destroying) vaccinia virus (VV) would be an appealing addition to the current therapies of cancers because of its ability to infect, replicate in, and lyse tumor cells, and spread to other tumor cells in successive rounds of replication. While clinical studies have demonstrated their safety, the antitumor efficacy of oncolytic VVs has been suboptimal. Oncolytic VVs' major mode of action is the destruction of tumor cells, which can subsequently activate a component of the immune system called T-cells that can travel to distant sites and target against any tumor they find. At present, virus spread through tumors, as well as the activation of tumor-specific T-cells, is limited, explaining the observed suboptimal antitumor activity of current oncolytic VVs. Thus it would be desirable to make the oncolytic VVs more powerful stimulators of immunity through activating resident T-cells within the tumors so that they will kill tumor cells and stop new tumors from growing. To activate T-cells within tumors, a new molecule called a T-cell engager that couples the T cell and the tumor cell, which increases the effectiveness of the T cells and their activation, has been constructed. This review summarizes the progress of the emerging field of combinations of oncolytic virotherapy and T-cell based therapy. ...
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Abstract: Gene transfer trials with adeno-associated virus (AAV) vectors have initiated to unveil the therapeutic potential of this approach, with some of the most exciting results coming from clinical studies of gene transfer for hemophilia B, congenital blindness, and the recent market approval of the first AAV-based gene therapy in Europe. With clinical development, however, some of the limitations of in vivo gene transfer have emerged; in particular the host immune system represents an important obstacle to be overcome in terms of both safety and efficacy of gene transfer in vivo with AAV vectors. Results in humans undergoing gene transfer indicate that capsid-specific T cell responses directed against transduced cells may limit the duration of transgene expression following AAV gene transfer, and similarly anti-AAV neutralizing antibodies can completely prevent transduction of a target tissue, resulting in lack of efficacy. Anti-AAV neutralizing antibodies are highly prevalent in humans, and the frequency of subjects with detectable titers can reach up to two thirds of the population. The approach to the problem of preexisting humoral immunity to AAV so far has been the exclusion of seropositive subjects, but this solution is far from being optimal. Several additional strategies have been proposed and tested in a variety of preclinical animal models. Future studies will help defining the optimal strategy, or combination of strategies, to successfully treat subjects with preexisting antibodies to AAV due to natural infection or to prior administration of AAV vectors. These advancements will likely have a significant impact on the field of gene transfer with AAV vectors. ...
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Specialty: Genetics, Gene TherapyInstitution: Department of Human and Molecular Genetics, Virginia Commonwealth University School of MedicineAddress: Richmond, Virginia, 23298, United States

Published on May 27, 2013

Abstract: Gene therapy provides a novel platform for therapeutic intervention of several genetic and non-genetic disorders. With the recent developments in the field, a wide variety of viral and non-viral vectors have emerged that can deliver genetic payloads to target cells. However, non-targeted delivery of transgenes often results in undesirable effects, low tumor transduction, and reduced therapeutic index. In this review, we focus on some of the novel approaches that can be used to meet the present challenges in the field and translate the potential of cancer gene therapy from 'bench to bedside' in the near future. ...
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Abstract: Congenital and acquired corneal opacities, and diseases of the ocular surface, are blinding conditions that impose physical, psychological, and financial constraints upon the sufferer. In the past, corneal and corneal epithelial stem cell transplantation have been the major treatment for severe corneal and ocular surface disease, respectively, but the sequelae of neovascularization and inflammatory eye disease cause many grafts to undergo irreversible immunological rejection. Furthermore, in the case of corneal dystrophies, the original disease may recur in the graft. New therapeutic options for diseases of the cornea and ocular surface are now being actively explored in experimental animals and in clinical trials. Antibody-based biologics are being tested for their ability to reduce blood and lymphatic vessel ingrowth into the cornea, and to reduce inflammation. Many new biomaterials are being examined for their capacity to transfer drugs and corneal epithelial cell progenitor cells to the ocular surface and anterior segment of the eye. New component-cell corneal transplantation procedures that may reduce the risk of immunological rejection have been developed and are already in clinical practice. Finally, gene therapy is being tested in experimental animals to improve the outcomes of corneal transplantation, and to halt or reverse the pathophysiology of some corneal dystrophies. ...
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